Role of Lactoferrin in Treatment of Bile Duct Ligation-Induced Hepatic Fibrosis in Rats: Impact on Inflammation and TGF-ß1/Smad2/α SMA Signaling Pathway.

Background: Hepatic fibrosis is a major health issue that might lead to hepatic cirrhosis and cancer. One of its main causes is cholestasis, which has been stimulated by bile duct ligation (BDL) to block the bile flow from the liver. As for the treatment, lactoferrin (LF), the iron-binding glycoprotein, has been evaluated in various studies for the treatment of infections, inflammation, and cancer. The current study aims to investigate the curative effects of LF on BDL-induced hepatic fibrosis in rats. Methods: Rats were randomly allocated into 4 groups: (1) Control sham, (2) BDL: that have been subjected to a surgery of BDL, (3) BDL + LF: 14 days later after surgery; they have been subjected to LF treatment (300 mg/kg/day, po) for two weeks, and (4) LF group has been administered (300 mg/kg/day, po) for two weeks. Results: BDL elevated inflammatory markers (tumor necrosis factor-alpha and interleukin -1beta (IL-1ß) by 635% and 250% (P ≤ 0.05), respectively, as sham group), beside it decreased the anti-inflammatory cytokine, interleukin- 10 (IL-10) by 47.7% (P ≤ 0.05) as sham group, causing inflammation, and fibrosis of the liver by the up-regulation of transforming growth factor-beta 1 (TGF-ß1)/Smad2/α-smooth muscle actin (SMA) signaling pathway. LF treatment ameliorated these effects through its anti-inflammatory action (it significantly decreased tumor necrosis factor-alpha and IL-1ß by 166% and 159% (P ≤ 0.05), respectively, as sham group, while increased IL-10 by 86.8% (P ≤ 0.05), as sham group) and anti-fibrotic effect by the down-regulation of TGF-ß1/Smad2/α-SMA signaling pathway. These results were confirmed by histopathological examination. Conclusion: lactoferrin shows promising results for the treatment of hepatic fibrosis via attenuating the TGF-ß1/Smad2/α-SMA pathway and through its properties.

Lactoferrin alleviates cyclophosphamide induced-nephropathy through suppressing the orchestration between Wnt4/ß-catenin and ERK1/2/NF-κB signaling and modulating klotho and Nrf2/HO-1 pathway.

AIMS: Cyclophosphamide is an alkylating agent with vast arrays of therapeutic activity. Currently, its medical use is limited due to its numerous adverse events, including nephrotoxicity. This study aimed to follow the molecular mechanisms behind the potential renoprotective action of lactoferrin (LF) against cyclophosphamide (CP)-induced renal injury. MATERIALS AND METHODS: For fulfillment of our aim, Spragw-Dwaly rats were orally administrated LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg). KEY FINDINGS: Treatment of CP-injured rats with LF significantly reduced the elevated creatinine and blood urea nitrogen (BUN), markedly upregulated Nrf2/HO-1 signaling with consequent increase in renal total antioxidant capacity (TAC) and decrease in renal malondialdehyde (MDA) level. Furthermore, LF treatment significantly reduced the elevated renal p-ERK1/2 expression, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB) levels in CP-treated animals. Interestingly, LF treatment downregulated Wnt4/ß-catenin signaling and increased both renal klotho gene expression and serum klotho level. Furthermore, LF treatment reduced apoptosis in kidney tissue via suppressing GSK-3ß expression and modulating caspase-3 and Bcl2 levels. Histopathological examination of kidney tissue confirmed the protective effect of LF against CP-induced renal injury. SIGNIFICANCE: The present findings document the renoprotective effect of LF against CP-induced nephropathy, which may be mediated via suppressing ERK1/2/ NF-κB and Wnt4/ß-catenin trajectories and enhancing klotho expression and Nrf2/HO-1 signaling.

Pramipexole and Lactoferrin ameliorate Cyclophosphamide-Induced haemorrhagic cystitis via targeting Sphk1/S1P/MAPK, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1ß signalling pathways and modulating the Nrf2/HO-1 pathway.

BACKGROUND: The use of cyclophosphamide (CP) as a chemotherapeutic agent is limited by its major complication haemorrhagic cystitis (HC). Finding preventive, safe, and efficient treatments for such problems is extensively ongoing. OBJECTIVE: This research aims to assess the uroprotective effect of pramipexole (PPX) and/or lactoferrin (LF) against CP-induced HC, in addition to shedding light on their possible molecular targets. METHODS: Adult male Sprague-Dawley rats were orally administered PPX (3 mg/kg) and/or LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg). RESULTS: Pretreatment of CP-intoxicated rats with either PPX or LF mitigated oxidative urinary bladder damage via upregulation of the Nrf2/HO-1 signalling pathway, resulting in a significant reduction in bladder MDA and 8-OHdG levels with concomitant elevations in SOD activity and GSH content. Simultaneously, both drugs markedly halted inflammation in bladder tissue through inhibition of the TLR4/NF-κB signalling pathway, followed by a significant decrease in inflammatory cytokine levels (TNF-α and IL-6). Interestingly, the PPX/LF protocol downregulated p-p38, p-ERK1/2, Sphk1, and S1P protein expression and inhibited the NLRP3/caspase1/IL-1ß axis. PPX/LF also significantly reduced BAX and caspase-3, in addition to increasing Bcl-2 levels in bladder tissue of CP-treated animals. These biochemical findings were supported by the improvement in the histological alterations induced by CP in the urinary bladder. CONCLUSIONS: The current study verified the protective effect of PPX and LF against CP-induced HC by halting oxidative stress, inflammation, and apoptosis. The molecular mechanism underlying this protective effect may involve targeting the crosstalk among Sphk1/S1P/MAPK/NF-κB, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1ß signalling pathways and modulating the Nrf2/HO-1 signalling pathway.

Fluoxetine ameliorates Alzheimer's disease progression and prevents the exacerbation of cardiovascular dysfunction of socially isolated depressed rats through activation of Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathway.

Depression is a risk factor for Alzheimer's (AD) and cardiovascular diseases (CVD). Therefore, depression treatment restricts its deteriorating effects on mood, memory and CV system. Fluoxetine is the most widely used antidepressant drug, it has neuroprotective effect through its antioxidant/anti-inflammatory properties. The current study investigated for the first-time the cross link between depression, AD and CVD besides, role of fluoxetine in mitigating such disorders. Depression was induced in rats by social isolation (SI) for 12 weeks, AlCL3 (70 mg/kg/day, i.p.) was used to induce AD which was administered either in SI or normal control (NC) grouped rats starting at 8th week till the end of the experiment, fluoxetine (10 mg/kg/day, p.o) treatment also was started at 8th week. SI and AD showed a statistically significant deteriorated effect on behavioral, neurochemical and histopathological analysis which was exaggerated when two disorder combined than each alone. Fluoxetine treatment showed protective effect against SI, AD and prevents exacerbation of CVD. Fluoxetine improved animals' behavior, increased brain monoamines, BDNF besides increased antioxidant defense mechanism of SOD, TAC contents and increased protein expression of Nrf2/HO-1 with significant decrease of AChE activity, ß-amyloid, Tau protein, MDA, TNF-α, IL1ß contents as well as decreased protein expression of NF-kB, TLR4, NLRP3 and caspase1. It also showed cardioprotective effects as it improved lipid profile with pronounced decrease of cardiac enzymes of CK-MB, troponin and MEF2. In conclusion, fluoxetine represents as a promising drug against central and peripheral disorders through its anti-inflammatory/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways.